WO2011061591A1 - Improved process for the preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanone)-2-yl)methyl piperidine hydrochloride form-iii - Google Patents
Improved process for the preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanone)-2-yl)methyl piperidine hydrochloride form-iii Download PDFInfo
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- WO2011061591A1 WO2011061591A1 PCT/IB2010/002916 IB2010002916W WO2011061591A1 WO 2011061591 A1 WO2011061591 A1 WO 2011061591A1 IB 2010002916 W IB2010002916 W IB 2010002916W WO 2011061591 A1 WO2011061591 A1 WO 2011061591A1
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- Prior art keywords
- donepezil hydrochloride
- form iii
- preparation
- indanone
- dimethoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
Definitions
- the present invention in general relates to improved process for preparing polymorphic form of l-benzyl-4-(5,6-dimethoxy-l-indanone)-2-yl)methyl piperidine hydrochloride (Donepezil hydrochloride). More particularly, the present invention provides an improved process for the preparation of Donepezil hydrochloride Form III in high yield and high purity.
- Donepezil Hydrochloride of formula I is first disclosed in US 4,895,841 is known for its excellent anti-acetyl-cholinesterase activity and it is an effective active ingredient in pharmaceutical preparations for treatment and prevention of diseases such as Alzheimer disease and senile dementia.
- US20050215591 disclosed Donepezil hydrochloride form HI and H2 along with Donepezil hydrochloride as monohydrate and sesquihydrate.
- US6,140,321 and US5,985,864 describes process for preparation of form III by recrystallizing Donepezil hydrochloride form I or by dissolving Donepezil hydrochloride form II in suitable solvent and precipitating the desired form by addition of an anti-solvent.
- Donepezil free base is dissolved in suitable solvent and treated with hydrochloric acid or hydrogen chloride or by humidification of any form to give desired form III, wherein all the processes disclosed contained use of large volumes of solvents, which is not only difficult to handle on the commercial scale but also pose environment hazards.
- US7,479,563 discloses a process for preparation of form III by dissolving Donepezil in ethanol and adding hydrochloric acid to get the desired form, the given process suffers a drawback of very long reaction time, which leads to the formation of impurities leading to decrease in purity levels.
- WO2009084030 discloses a process for preparation of Donepezil hydrochloride form III using methanol/acetone, but the process is not compatible at industrial scale as it too uses large volumes of solvents, which is an environment and economical hazard.
- an improved process for preparation of l-benzyl-4-(5,6-dimethoxy-l-indanone)-2- yl)methyl piperidine hydrochloride (Donepezil hydrochloride) form III comprising dissolving Donepezil hydrochloride in an halogenated solvent to prepare a solution, removing the solvent to obtain solid residue, adding alcoholic solvent to precipitate Donepezil hydrochloride form III and isolating the precipitated Donepezil hydrochloride form III.
- Donepezil hydrochloride as used in step (a) can be prepared from any of the processes described in prior art.
- Halogenated solvent used in step (a) is selected from the group comprising of dichloromethane, dichloroethane, chloroform and the like.
- Step (a) Reaction of step (a) is carried out at temperature range of 20-50°C and preferably 30-40°C.
- Alcoholic solvent used in step (c) can be selected from C1-C4 alcohol.
- the said alcohol is selected from the group comprising of methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol and the like or mixture thereof.
- Isolation of Donepezil hydrochloride form III in step (d) is performed by any conventional method like filtration.
- donepezil hydrochloride form III obtained by the process described herein possess the relative particle size distribution as having D(0.1) not more than 10 ⁇ ⁇ and D(0.9) not more than 500 ⁇ .
- the present invention also provides the median particle size D(0.5) of donepezil hydrochloride form III of not more than 200 ⁇ .
- D(0.9) as used herein is defined as a size of particles where 90 volume percent of the particles have sizes less than the value given.
- D(0.5) defines a size where 50 volume percent of the particles have sizes less than the specified value.
- D(0.1) defines a size where 10 volume percent of the particles have sizes less than the specified value.
- Donepezil hydrochloride (25 g) was taken in dichloromethane (125 ml) at 25-
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Disclosed herein an improved process for the preparation of polymorphic form III of Donepezil hydrochloride.
Description
IMPROVED PROCESS FOR THE PREPARATION OF l-BENZYL-4-(5,6- DIMETHOXY-l-INDANONE)-2-YL)METHYL PIPERIDINE
HYDROCHLORIDE FORM-III
FIELD OF INVENTION
The present invention in general relates to improved process for preparing polymorphic form of l-benzyl-4-(5,6-dimethoxy-l-indanone)-2-yl)methyl piperidine hydrochloride (Donepezil hydrochloride). More particularly, the present invention provides an improved process for the preparation of Donepezil hydrochloride Form III in high yield and high purity.
BACKGROUND OF THE INVENTION
Donepezil Hydrochloride of formula I is first disclosed in US 4,895,841 is known for its excellent anti-acetyl-cholinesterase activity and it is an effective active ingredient in pharmaceutical preparations for treatment and prevention of diseases such as Alzheimer disease and senile dementia.
As Donepezil hydrochloride is administered orally, thus its stability against heat and humidity during storage was an important concern, thus a stable form was always desirable, subsequently, US 5,985,864 disclosed five crystalline forms of Donepezil hydrochloride, i.e. I, II, III, IV and V as a result of extensive research to achieve stable form of Donepezil hydrochloride.
US7, 186,842 disclosed novel polymorphic form of Donepezil hydrochloride as form VI.
US20050215591 disclosed Donepezil hydrochloride form HI and H2 along with Donepezil hydrochloride as monohydrate and sesquihydrate.
Recently, US2009137811 disclosed Donepezil hydrochloride as hemihydrate and dihydrate.
Each of the disclosed forms have distinct intrinsic powder X-ray diffraction pattern, infra-red spectrum and other properties, but of all the forms, form III of Donepezil hydrochloride has more marked characteristics than other crystal types; specifically it has low hygroscopicity and higher heat stability. Keeping this in view many processes has been developed for the preparation of form III.
US6,140,321 and US5,985,864 describes process for preparation of form III by recrystallizing Donepezil hydrochloride form I or by dissolving Donepezil hydrochloride form II in suitable solvent and precipitating the desired form by addition of an anti-solvent. Alternatively Donepezil free base is dissolved in suitable solvent and treated with hydrochloric acid or hydrogen chloride or by humidification of any form to give desired form III, wherein all the processes disclosed contained use of large volumes of solvents, which is not only difficult to handle on the commercial scale but also pose environment hazards.
US7,479,563 discloses a process for preparation of form III by dissolving Donepezil in ethanol and adding hydrochloric acid to get the desired form, the given process suffers a drawback of very long reaction time, which leads to the formation of impurities leading to decrease in purity levels.
WO2009084030 discloses a process for preparation of Donepezil hydrochloride form III using methanol/acetone, but the process is not compatible at industrial scale as it too uses large volumes of solvents, which is an environment and economical hazard.
Thus, from the preceding literature it is apparent that the processes suffer incompatibilities in terms of being applicable at industrial level.
Thus, there is a continuing <need for the development of eco-friendly and cost effective process for the preparation of Donepezil hydrochloride form III that is devoid of the limitation of the processes known in the prior art.
OBJECT AND SUMMARY OF THE INVENTION
It is an object of the present invention to improve upon limitations in the prior art by providing a commercially viable and environment friendly process for producing Donepezil hydrochloride form III in high yield and high purity.
In accordance with one preferred embodiment of the present invention, there is provided a process for the preparation of polymorphic form III of l-benzyl-4-(5,6-
dimethoxy-l-indanone)-2-yl)methyl piperidine hydrochloride (Donepezil hydrochloride) comprising the steps of:
a) mixing Donepezil hydrochloride and halogenated solvent;
b) removing the halogenated solvent;
c) adding alcoholic solvent and
d) isolating the polymorphic form III of Donepezil hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
According to one embodiment of the present invention, there is provided an improved process for preparation of l-benzyl-4-(5,6-dimethoxy-l-indanone)-2- yl)methyl piperidine hydrochloride (Donepezil hydrochloride) form III, comprising dissolving Donepezil hydrochloride in an halogenated solvent to prepare a solution, removing the solvent to obtain solid residue, adding alcoholic solvent to precipitate Donepezil hydrochloride form III and isolating the precipitated Donepezil hydrochloride form III.
In accordance with one preferred embodiment of the present invention, there is provided a process for the preparation of polymorphic form III of l-benzyl-4-(5,6- dimethoxy- 1 -indanone)-2-yl)methyl piperidine hydrochloride (Donepezil hydrochloride) comprising the steps of:
a) mixing Donepezil hydrochloride and halogenated solvent;
b) removing the halogenated solvent;
c) adding alcoholic solvent and
d) isolating the polymorphic form III of Donepezil hydrochloride.
Donepezil hydrochloride, as used in step (a) can be prepared from any of the processes described in prior art.
Halogenated solvent used in step (a) is selected from the group comprising of dichloromethane, dichloroethane, chloroform and the like.
Reaction of step (a) is carried out at temperature range of 20-50°C and preferably 30-40°C.
Alcoholic solvent used in step (c) can be selected from C1-C4 alcohol. The said alcohol is selected from the group comprising of methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol and the like or mixture thereof.
Isolation of Donepezil hydrochloride form III in step (d) is performed by any conventional method like filtration.
According to a further embodiment of the present invention, donepezil hydrochloride form III obtained by the process described herein possess the relative particle size distribution as having D(0.1) not more than 10 μιη and D(0.9) not more than 500 μηι. The present invention also provides the median particle size D(0.5) of donepezil hydrochloride form III of not more than 200 μηι.
The term "particle size distribution" as used herein refers to the relative percentages by weight or volume of each of the different size fractions of a particulate matter. The term "median particle; size" as used herein refers to the median or 50% quantile of a particle size distribution.
The term D(0.9) as used herein is defined as a size of particles where 90 volume percent of the particles have sizes less than the value given. The term D(0.5) defines a size where 50 volume percent of the particles have sizes less than the specified value. The term D(0.1) defines a size where 10 volume percent of the particles have sizes less than the specified value.
The process for the preparation of form III of Donepezil hydrochloride described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Example 1
Preparation of Donepezil Hydrochloride Polymorphic Crystalline Form III
Donepezil hydrochloride (80 g) was taken in dichloromethane (400 ml) at 25- 30 °C. The resulting solution was heated to 35-40°C. The dichloromethane was distilled off completely under vacuum below 40°C and the resulting residue was kept under vacuum for 30 minutes. To the resulting residue, isopropanol (560 ml) was added and heated to reflux, under stirring for 1 hour at reflux temperature. The resulting reaction mass was cooled to 20-25 °C and stirred for 1 hour. The resulting solid was filtered, suck dried, washed with isopropanol (240 ml) and finally dried under vacuum at 50-55°C to afford 64 g of the title compound. HPLC purity 99.9%.
The relative particle size distribution is having D(0.1) = 5.127 μηι, D(0.5) = 58.714 μηι and D(0.9) = 253.628 μιη.
Example 2
Preparation of Donepezil Hydrochloride Polymorphic Crystalline Form III
Donepezil hydrochloride (50 g) was taken in dichloromethane. (250 ml) at 25-
30 °C. The resulting solution was heated to 35-40°C. The dichloromethane was distilled off completely under vacuum below 40°C and the resulting residue was kept under vacuum for 30 minutes. To the resulting residue, methanol (350 ml) was added and heated to reflux, under stirring for 1 hour at reflux temperature. The resulting reaction mass was cooled to 20-25 °C and stirred for 1 hour. Distilled 175 ml of methanol under vacuum at 43°C, and cooled to 20-25 °C. Seeded with 0.5 g of Donepezil hydrochloride Form III. Stirred for 2 h at 20-25°C, and solid comes out. The resulting solid was filtered, suck dried, washed with methanol (25 ml) and finally dried under vacuum at 50-55°C to afford 31 g of the title compound.
Example 3
Preparation of Donepezil Hydrochloride Polymorphic Crystalline Form III
Donepezil hydrochloride (40 g) was taken in chloroform (200 ml) at 25-30 °C. The resulting solution was heated to 35-40°C. The chloroform was distilled off completely under vacuum below 40°C and the resulting residue was kept under vacuum for 30 minutes. To the resulting residue, isopropanol (280 ml) was added and heated to reflux, under stirring for 1 hour at reflux temperature. The resulting reaction mass was cooled to 20-25 °C and stirred for 1 hour. The resulting solid was filtered, suck dried, washed with isopropanol (120 ml) and finally dried under vacuum at 50- 55°C to afford 31.5 g of the title compound.
Example 4
Preparation of Donepezil Hydrochloride Polymorphic Crystalline Form III
Donepezil hydrochloride (40 g) was taken in dichloroethane (200 ml) at 25-30 °C. The resulting mixture was heated to 50° C. The dichloroethane was distilled off completely under vacuum below 50°C and the resulting residue was kept under vacuum for 30 minutes. To the resulting residue, isopropanol (280 ml) was added and heated to reflux, under stirring for 1 hour at reflux temperature. The resulting reaction mass was cooled to 20-25 °C and stirred for 1 hour. The resulting solid was filtered,
suck dried, washed with isopropanol (120 ml) and finally dried under vacuum at 50- 55 °C to afford 32 g of the title compound.
Example 5
Preparation of Donepezil Hydrochloride Polymorphic Crystalline Form III
Donepezil hydrochloride (25 g) was taken in dichloromethane (125 ml) at 25-
30 °C. The resulting mixture was heated to 35-40°C. The dichloromethane was distilled off completely under vacuum below 40° C and the resulting residue was kept under vacuum for 30 minutes. To the resulting residue, n-butanol (100 ml) was added and heated to reflux, under stirring for 1 hour at reflux temperature. The resulting reaction mass was cooled to 20-25 °C and stirred for 1 hour. The resulting solid was filtered, suck dried, washed with n-butanol (25 ml) and finally dried under vacuum at 50-55°C to afford 22 g of the title compound.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.
Claims
1. A process for the preparation of polymorphic form III of l-benzyl-4-(5,6- dimethoxy-l-indanone)-2-yl)methyl piperidine hydrochloride (Donepezil hydrochloride) comprising the steps of:
a) mixing Donepezil hydrochloride and halogenated solvent;
b) removing the halogenated solvent;
c) adding alcoholic solvent and
d) isolating the polymorphic form III of Donepezil hydrochloride.
2. The process according to claim 1, wherein the halogenated solvent used in step (a) is selected from the group comprising of dichloromethane, dichloroethane and chloroform.
3. The process according to claim 2, wherein the preferred halogenated solvent is dichloromethane.
4. The process according to claim 1, wherein the alcoholic solvent used in step (c) is selected from Ci-C4 alcohol.
5. The process according to claim 4, wherein the alcoholic solvent used is selected from the group comprising of methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol or mixture thereof.
6. The process according to claim* 5, wherein the preferred alcoholic solvent is iso- propanol.
7. The process according to claim 1, wherein reaction temperature in step (a) is 20- 50°C and preferably 30-40°C.
8. The particle size of polymorphic form III of l-benzyl-4-(5,6-dimethoxy-l- indanone)-2-yl)methyl piperidine hydrochloride (Donepezil hydrochloride) according to claim 1 is having D(0.1) not more than 10 μιη, D(0.5) not more than 200 μιη and D(0.9) not more than 500 μηι.
9. A process for the preparation of polymorphic form III of l-benzyl-4-(5,6- dimethoxy- 1 -indanone)-2-yl)methyl piperidine hydrochloride (Donepezil hydrochloride) comprising the steps of:
a) mixing Donepezil hydrochloride and dichloromethane;
b) removing the dichloromethane;
c) adding iso-propanol and 1
d) isolating the polymorphic form III of Donepezil hydrochloride.
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| Application Number | Priority Date | Filing Date | Title |
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| IN2379/DEL/2009 | 2009-11-18 | ||
| IN2379DE2009 | 2009-11-18 |
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| WO2011061591A1 true WO2011061591A1 (en) | 2011-05-26 |
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4895841A (en) | 1987-06-22 | 1990-01-23 | Eisai Co., Ltd. | Cyclic amine compounds with activity against acetylcholinesterase |
| US5985864A (en) | 1996-06-07 | 1999-11-16 | Eisai Co., Ltd. | Polymorphs of donepezil hydrochloride and process for production |
| US6140321A (en) | 1996-06-07 | 2000-10-31 | Eisai Co., Ltd. | Polymorphs of donepezil hydrochloride and process for production |
| EP1323712A1 (en) * | 2000-09-25 | 2003-07-02 | Eisai Co., Ltd. | Process for producing multiform crystal of donepezil hydrochloride |
| WO2004092137A1 (en) * | 2003-04-16 | 2004-10-28 | Hetero Drugs Limited | Novel crystalline forms of donepezil hydrochloride |
| WO2006111983A2 (en) * | 2005-04-21 | 2006-10-26 | Jubilant Organosys Limited | NOVEL POLYMORPHIC FORM OF (l-BENZYL-4-[(5,6-DIMETHOXY-l- INDANONE)-2-YL]METHYL PIPERIDINE HYDROCHLORIDE AND PROCESS FOR PREPARING THE SAME |
| US7186842B2 (en) | 2003-02-12 | 2007-03-06 | Usv, Ltd. | Polymorph of (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-y1] methyl piperidine hydrochloride (Donepezil hydrochloride) and a process for producing thereof |
| US20090137811A1 (en) | 2005-07-30 | 2009-05-28 | Pliva Hrvatska D.O.O | Process for the preparation of donepezil and intermediate compounds thereof as well as hydrates of donepezil |
| WO2009084030A2 (en) | 2007-12-03 | 2009-07-09 | Neuland Laboratories Ltd. | Improved process for the preparation of (1-benzyl-4-(5,6,- dimethoxyind anone-2-yl)methylpiperidine) hydrochloride-form iii |
-
2010
- 2010-11-16 WO PCT/IB2010/002916 patent/WO2011061591A1/en not_active Ceased
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4895841A (en) | 1987-06-22 | 1990-01-23 | Eisai Co., Ltd. | Cyclic amine compounds with activity against acetylcholinesterase |
| US5985864A (en) | 1996-06-07 | 1999-11-16 | Eisai Co., Ltd. | Polymorphs of donepezil hydrochloride and process for production |
| US6140321A (en) | 1996-06-07 | 2000-10-31 | Eisai Co., Ltd. | Polymorphs of donepezil hydrochloride and process for production |
| EP1323712A1 (en) * | 2000-09-25 | 2003-07-02 | Eisai Co., Ltd. | Process for producing multiform crystal of donepezil hydrochloride |
| US7479563B2 (en) | 2000-09-25 | 2009-01-20 | Eisai R&D Management Co., Ltd. | Method of producing polymorphic crystals of donepezil hydrochloride |
| US7186842B2 (en) | 2003-02-12 | 2007-03-06 | Usv, Ltd. | Polymorph of (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-y1] methyl piperidine hydrochloride (Donepezil hydrochloride) and a process for producing thereof |
| WO2004092137A1 (en) * | 2003-04-16 | 2004-10-28 | Hetero Drugs Limited | Novel crystalline forms of donepezil hydrochloride |
| US20050215591A1 (en) | 2003-04-16 | 2005-09-29 | Hetero Drugs Limited | Novel crystalline forms of donepezil hydrochloride |
| WO2006111983A2 (en) * | 2005-04-21 | 2006-10-26 | Jubilant Organosys Limited | NOVEL POLYMORPHIC FORM OF (l-BENZYL-4-[(5,6-DIMETHOXY-l- INDANONE)-2-YL]METHYL PIPERIDINE HYDROCHLORIDE AND PROCESS FOR PREPARING THE SAME |
| US20090137811A1 (en) | 2005-07-30 | 2009-05-28 | Pliva Hrvatska D.O.O | Process for the preparation of donepezil and intermediate compounds thereof as well as hydrates of donepezil |
| WO2009084030A2 (en) | 2007-12-03 | 2009-07-09 | Neuland Laboratories Ltd. | Improved process for the preparation of (1-benzyl-4-(5,6,- dimethoxyind anone-2-yl)methylpiperidine) hydrochloride-form iii |
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